title: CRL4A-FBXW5-mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth.
abstract: DLC1 encodes a RhoA GTPase-activating protein and tumor suppressor lost in cancer by genomic deletion or epigenetic silencing and loss of DLC1 gene transcription. We unexpectedly identified non-small cell lung cancer (NSCLC) cell lines and tumor tissue that expressed DLC1 mRNA yet lacked DLC1 protein expression. We determined that DLC1 was ubiquitinated and degraded by cullin 4A-RING ubiquitin ligase (CRL4A) complex interaction with DDB1 and the FBXW5 substrate receptor. siRNA-mediated suppression of cullin 4A, DDB1, or FBXW5 expression restored DLC1 protein expression in NSCLC cell lines. FBXW5 suppression-induced DLC1 reexpression was associated with a reduction in the levels of activated RhoA-GTP and in RhoA effector signaling. Finally, FBXW5 suppression caused a DLC1-dependent decrease in NSCLC anchorage-dependent and -independent proliferation. In summary, we identify a posttranslational mechanism for loss of DLC1 and a linkage between CRL4A-FBXW5-associated oncogenesis and regulation of RhoA signaling.
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Pharmacology, and Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
authors.forename: Tai Young
authors.initials: TY
authors.lastname: Kim
authors.forename: Sarah
authors.initials: S
authors.lastname: Jackson
authors.forename: Yue
authors.initials: Y
authors.lastname: Xiong
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Whitsett
authors.forename: Janine R
authors.initials: JR
authors.lastname: Lobello
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Nhan Le
authors.initials: NL
authors.lastname: Tran
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; C091435:DDB1 protein, human; C112352:DLC1 protein, human; D004268:DNA-Binding Proteins; D044783:F-Box Proteins; C528759:FBXW5 protein, human; D020690:GTPase-Activating Proteins; D009097:Multienzyme Complexes; D025521:Tumor Suppressor Proteins
keywords: Rho GTPase-activating protein 7; Rho-selective GTPase-activating protein; STARD12